Antimicrobial Drugs PDF

47 C H A P T E R Antimycobacterial Drugs *...

47 C H A P T E R Antimycobacterial Drugs * Camille E. Beauduy, PharmD, & Lisa G. Winston, MD C ASE STUDY A 60-year-old man presents to the emergency department tuberculosis, the patient is placed in respiratory isolation. with a 2-month history of fatigue, weight loss (10 kg), fevers, His first sputum smear shows many acid-fast bacilli, and an night sweats, and a productive cough. He is currently living HIV test returns with a positive result. What drugs should with friends and has been intermittently homeless, spending be started for treatment of presumptive pulmonary tubercu- time in shelters. He reports drinking about six beers per day. losis? Does the patient have a heightened risk of developing In the emergency department, a chest x-ray shows a right medication toxicity? If so, which medication(s) would be apical infiltrate. Given the high suspicion for pulmonary likely to cause toxicity? Mycobacteria are intrinsically resistant to most antibiotics. Because are the most active drugs. An isoniazid-rifampin combina- they grow more slowly than other bacteria, antibiotics that are tion administered for 9 months will cure 95–98% of cases of most active against rapidly growing cells are relatively ineffective. tuberculosis caused by susceptible strains. An initial intensive Mycobacterial cells can also be dormant and, thus, resistant to phase of treatment is recommended for the first 2 months due many drugs or killed only very slowly. The lipid-rich mycobacte- to the prevalence of resistant strains. The addition of pyrazin- rial cell wall is impermeable to many agents. Mycobacterial species amide during this intensive phase allows the total duration of are intracellular pathogens, and organisms residing within macro- therapy to be reduced to 6 months without loss of efficacy. phages are inaccessible to drugs that penetrate these cells poorly. In practice, therapy is usually initiated with a four-drug regi- Finally, mycobacteria are notorious for their ability to develop men of isoniazid, rifampin, pyrazinamide, and ethambutol resistance. Combinations of two or more drugs are required to until susceptibility of the clinical isolate has been determined. overcome these obstacles and to prevent emergence of resistance In susceptible isolates, the continuation phase consists of an during the course of therapy. The response of mycobacterial infec- additional 4 months with isoniazid and rifampin (Table 47–2). tions to chemotherapy is slow, and treatment must be adminis- Neither ethambutol nor other drugs such as streptomycin adds tered for months to years, depending on which drugs are used. The substantially to the overall activity of the regimen (ie, the dura- drugs used to treat tuberculosis, atypical mycobacterial infections, tion of treatment cannot be further reduced if another drug is and leprosy are described in this chapter. used), but the fourth drug provides additional coverage if the isolate proves to be resistant to isoniazid, rifampin, or both. If therapy is initiated after the isolate is known to be suscep- DRUGS USED IN TUBERCULOSIS tible to isoniazid and rifampin, ethambutol does not need to be added. The prevalence of isoniazid resistance among clini- Isoniazid (INH), rifampin (or other rifamycin), pyrazin- cal isolates in the USA is approximately 10%. Prevalence of amide, and ethambutol are the traditional first-line agents for resistance to both isoniazid and rifampin (termed multidrug treatment of tuberculosis (Table 47–1). Isoniazid and rifampin resistance) was 1.9% in the USA in 2017, and it has remained stable for approximately 20 years. Multidrug resistance is much * The authors thank Henry F. Chambers, MD, and Daniel H. Deck, more prevalent in many other parts of the world. Resistance to PharmD, for their contributions to previous editions. rifampin alone is rare. 875 Katzung_Ch47_p0875-0886.indd 875 25/08/20 1:14 PM  876    SECTION VIII Chemotherapeutic Drugs TABLE 47–1 Antimicrobials used in the treatment of In vitro, isoniazid inhibits most tubercle bacilli at a concentra- tuberculosis. tion of 0.2 mcg/mL or less and is bactericidal for actively growing tubercle bacilli. It is less effective against nontuberculous mycobac- Drug Typical Adult Dosage1 teria. Isoniazid penetrates into macrophages and is active against First-line agents both extracellular and intracellular organisms. Isoniazid 300 mg/d Rifampin 600 mg/d Mechanism of Action & Basis of Resistance Pyrazinamide 25 mg/kg/d Isoniazid inhibits synthesis of mycolic acids, which are essential Ethambutol 15–25 mg/kg/d components of mycobacterial cell walls. Isoniazid is a prodrug that Second-line agents is activated by KatG, the mycobacterial catalase-peroxidase. The Amikacin 15 mg/kg/d activated form of isoniazid forms a covalent complex with an acyl Aminosalicylic acid 8–12 g/d carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis. Resistance to isoni- Bedaquiline 400 mg/d azid is associated with mutations resulting in overexpression of inhA, Capreomycin 15 mg/kg/d which encodes an NADH-dependent acyl carrier protein reductase; Clofazimine 200 mg/d mutation or deletion of the katG gene; promoter mutations result- Cycloserine 500–1000 mg/d, divided ing in overexpression of ahpC, a gene involved in protection of the Ethionamide 500–750 mg/d cell from oxidative stress; and mutations in kasA. Overproducers of Levofloxacin 500–750 mg/d inhA express low-level isoniazid resistance and cross-resistance to ethionamide. KatG mutants express high-level isoniazid resistance Linezolid 600 mg/d and often are not cross-resistant to ethionamide. Moxifloxacin 400 mg/d Drug-resistant mutants are normally present in susceptible Pretomanid 200 mg/d mycobacterial populations at about 1 bacillus in 106. Since Rifabutin 2 300 mg/d tuberculous lesions often contain more than 108 tubercle bacilli, Rifapentine3 600 mg once weekly resistant mutants are readily selected if isoniazid or any other Streptomycin 15 mg/kg/d drug is given as a single agent. The use of two independently 1 acting drugs in combination is much more effective. The prob- Assuming normal renal function. 2 ability that a bacillus is initially resistant to both drugs is approxi- 150 mg/d if used concurrently with a protease inhibitor or cobicistat; 600 mg/d with efavirenz. mately 1 in 106 × 106, or 1 in 1012, several orders of magnitude 3 No longer recommended, but may be considered in selected cases if HIV-uninfected greater than the number of infecting organisms. Thus, at least without cavitation on chest radiograph. two (or more in certain cases) active agents should always be used to treat active tuberculosis to prevent emergence of resis- tance during therapy. ISONIAZID Isoniazid is the most active drug for the treatment of tuberculo- Pharmacokinetics sis caused by susceptible strains. It is a small molecule (molecular weight 137) that is freely soluble in water. The structural similarity Isoniazid is readily absorbed from the gastrointestinal tract, opti- to pyridoxine is shown below. mally on an empty stomach; peak concentrations may be decreased by up to 50% when taken with a fatty meal. A 300-mg oral dose N (5 mg/kg in children) achieves peak plasma concentrations of 3–5 mcg/mL within 1–2 hours. Isoniazid diffuses readily into all body fluids and tissues. The concentration in the central nervous system and cerebrospinal fluid ranges between 20% and 100% of simultaneous serum concentrations. CONHNH2 Metabolism of isoniazid, especially acetylation by liver N-acet- Isoniazid yltransferase, is genetically determined (see Chapter 4). The aver- age plasma concentration of isoniazid in rapid acetylators is about one third to one half of that in slow acetylators, and average half- N lives are less than 1 hour and 3 hours, respectively. More rapid CH3 clearance of isoniazid by rapid acetylators is usually of no thera- OH peutic consequence when appropriate doses are administered daily, HOH2C but subtherapeutic concentrations may occur if drug is adminis- CH2OH tered as a once-weekly dose or if there is malabsorption. Isoniazid metabolites and a small amount of unchanged drug Pyridoxine are excreted in the urine. The dosage need not be adjusted in renal Katzung_Ch47_p0875-0886.indd 876 25/08/20 1:14 PM  CHAPTER 47 Antimycobacterial Drugs    877 TABLE 47–2 Recommended treatment for drug-susceptible tuberculosis. Intensive Phase Continuation Phase Regimen (min duration = 8 weeks) (min duration = 18 weeks)1 (in order of preference) Drugs Dosing Interval Drugs Dosing Interval Comments 2 2 1 INH 7 days per week INH 7 days per week Preferred regimen. RIF RIF PZA EMB 2 INH 7 days per week2 INH 3 days per week Preferred alternative if less frequent RIF RIF DOT is needed. PZA EMB 3 INH 3 days per week INH 3 days per week Caution in patients with HIV and/or RIF RIF cavitary disease due to concerns for treatment failure, relapse, drug PZA resistance. EMB 4 INH 7 days per week × INH 2 days per week Avoid in patients with HIV or those RIF 2 weeks, then RIF with smear-positive and/or cavitary 2 days per week × disease. PZA 6 weeks EMB 1 Experts recommend prolonged continuation phase (31 weeks) for patients with cavitation on initial chest radiograph and positive cultures at the end of the intensive treatment phase. 2 May consider 5 days per week if needed for DOT. No studies compare 5 versus 7 doses per week, but extensive experience suggests efficacy of this regimen. DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin. failure. Dose adjustment is not well defined in patients with severe A. Immunologic Reactions preexisting hepatic insufficiency and should be guided by serum Fever and skin rashes are occasionally seen. Drug-induced systemic concentrations if a reduction in dose is contemplated. Isoniazid lupus erythematosus has been reported. inhibits several cytochrome P450 enzymes, leading to increased concentrations of such medications as phenytoin, carbamazepine, B. Direct Toxicity and benzodiazepines. However, when used in combination with Isoniazid-induced hepatitis is the most common major toxic effect. rifampin, a potent CYP enzyme inducer, the concentrations of This is distinct from the minor increases in liver aminotransferases these medications are usually decreased. (up to three or four times normal), which do not require cessation of the drug and which are seen in 10–20% of patients, who usually Clinical Uses are asymptomatic. Clinical hepatitis with loss of appetite, nausea, The typical dosage of isoniazid is 5 mg/kg/d; a typical adult dose vomiting, jaundice, and right upper quadrant pain occurs in 1% of is 300 mg given once daily. Up to 10 mg/kg/d may be used for isoniazid recipients and can be fatal, particularly if the drug is not serious infections or if malabsorption is a problem. A 15-mg/kg discontinued promptly. Isoniazid-induced hepatitis is associated dose, or 900 mg, may be used in a twice to three times-weekly dos- with histologic evidence of hepatocellular damage and necrosis. ing regimen in combination with a second antituberculous agent The risk of hepatitis depends on age. It occurs rarely under age 20, (eg, rifampin, 600 mg). Pyridoxine, 25–50 mg/d, is recommended in 0.3% of those age 21–35, 1.2% of those age 36–50, and 2.3% for those with conditions predisposing to neuropathy, an adverse in those age 50 and above. The risk of hepatitis is greater in indi- effect of isoniazid. Isoniazid is usually given by mouth but can be viduals with alcohol use disorders and possibly during pregnancy given parenterally in the same dosage. and the postpartum period. Development of isoniazid hepatitis Isoniazid as a single agent is also indicated for treatment of contraindicates further use of the drug. latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg Peripheral neuropathy is observed in 10–20% of patients given twice weekly, and the duration is usually 9 months. dosages >5 mg/kg/d, but it is infrequently seen with the standard 300-mg adult dose. Peripheral neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions such Adverse Reactions as malnutrition, alcohol use disorder, diabetes, AIDS, and end- The incidence and severity of untoward reactions to isoniazid are stage renal disease. Neuropathy is due to a relative pyridoxine related to dosage and duration of administration. deficiency. Isoniazid promotes excretion of pyridoxine, and this Katzung_Ch47_p0875-0886.indd 877 25/08/20 1:14 PM  878    SECTION VIII Chemotherapeutic Drugs toxicity is readily reversed by administration of pyridoxine in a Clinical Uses dosage as low as 10 mg/d. Central nervous system toxicity, which A. Mycobacterial Infections is less common, includes memory loss, psychosis, ataxia, and sei- zures. These effects may also respond to pyridoxine. Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be admin- Miscellaneous other reactions include hematologic abnormali- istered with isoniazid or other antituberculous drugs to patients ties, provocation of pyridoxine deficiency anemia, tinnitus, and with active tuberculosis to prevent emergence of drug-resistant gastrointestinal discomfort. mycobacteria. In some short-course therapies, 600 mg of rifampin is given twice weekly. Rifampin, 600 mg daily or twice weekly for 6 months, is also effective in combination with other agents in RIFAMPIN some atypical mycobacterial infections and in leprosy. Rifampin, 600 mg daily for 4 months as a single drug, is an effective treat- Rifampin is a semisynthetic derivative of rifamycin, an antibi- ment for latent tuberculosis. otic produced by Amycolatopsis rifamycinica, formerly named Streptomyces mediterranei. It is active in vitro against gram-positive B. Other Indications organisms, some gram-negative organisms, such as Neisseria and Rifampin has other uses in bacterial infections. An oral dosage Haemophilus species, mycobacteria, and chlamydiae. Susceptible of 600 mg twice daily for 2 days can eliminate meningococcal organisms are inhibited by